Project Summary/Abstract Despite recent advances in both diagnostic and therapeutic modalities, long-term prognosis for patients affected by advanced stage head and neck squamous cell carcinoma (HNSCC) remains dismal with 5-year survival less than 40%. This grim prognosis is in distinct contrast to the more than 80% chance of cure for those patients who present with early stage cancer. Unfortunately, more than two-third of patients are diagnosed only after the disease is advanced. Failure to diagnose this cancer early is mainly attributed to the unavailability of a screening test for high risk patients as well as frequent misdiagnosis of early stage cancer. Thus, there is a need for a simple and noninvasive test, widely accessible to physicians in the primary care setting, which can be used to screen (in asymptomatic patients) and diagnose (in symptomatic patients) HNSCC in high risk population to improve early detection. We have previously demonstrated the feasibility of cancer detection based on analysis of patterns of serum IgG immunoreactivity against a panel of 130 cancer- specific antigens. These markers were selected using microarray-based serological profiling and specialized bioinformatics. Use of this modeling strategy on an independent set of serum samples resulted in an accuracy of 84.9% with sensitivity of 79.8% and specificity of 90.1%. The preliminary results are promising and support our rationale and objective for this proposed research which is to refine and validate this diagnostic strategy for early HNSCC detection in high risk population based on analysis of pattern of serum and salivary immunoreactivity (IgA and IgG) against a panel of diagnostic biomarkers. Specific aims are: 1) expand and select key diagnostic biomarkers via new strategies using microarray-based serological and salivary profiling and specialized bioinformatics. The hypothesis here, supported by our preliminary data, is that by increasing the number and diversity of biomarkers available for selection, an improved panel of biomarkers can be formulated to improve the overall accuracy of this diagnostic strategy; 2) validate the clinical utility of this diagnostic strategy for early cancer detection in high risk patient population. A final panel of diagnostic biomarkers which can reliably distinguish sera of early stage cancer patients from high risk patients based on serum- and/or salivary-based assays will be formulated. The ability of this diagnostic strategy for early cancer detection will then be assessed in a retrospective repository study involving a group of high risk patients who have been followed on a regular basis with serial collection of serum and saliva samples and known cancer status (presence or absence of cancer diagnosis) at their last follow-up. Significance: We expect to successfully refine and validate this diagnostic platform which will then set the stage for large multi-institutional prospective screening trials. The implementation of a simple and noninvasive assay for early cancer detection is expected to have an important positive impact on improving the survival as well as quality of life of the approximately 45,660 patients diagnosed with this devastating disease each year in the United States. PUBLIC HEALTH RELEVANCE: Project Narrative Cancer is the second leading cause of death among veterans. An estimated 175,000 veterans have cancer and approximately 35,000 new cases of cancer are diagnosed in the VA each year. According to the report from VA Central Cancer Registry (VACCR), head and neck cancer consistently ranked as the third most common cancer affecting the VA population. A disproportionate number of veterans are at increased risk for development of head and neck cancer because of their older age, male gender, and greater consumption of tobacco and alcohol. Unfortunately, a majority of these patients are diagnosed only after the disease is advanced due to the unavailability of an effective test for screening and early detection of this disease. Even after enduring radical treatments which often result in significant physical disfigurement as well as dysfunction of speech, breathing, and swallowing, these patients' prognosis remains dismal with 5-year survival of less than 40%. This grim prognosis is in distinct contrast to the more than 80% chance of cure for patients who present with early stage cancer. This dramatic difference in survival and quality of life underlies the importance of early detection. In this proposal, we plan to develop a test for screening and early detection of head and neck cancer, using biological fluids such as blood and saliva which are easily accessible. The implementation of this diagnostic assay for early cancer detection is expected to have an important positive impact on improving the survival as well as quality of life of the veterans as well as the 45,660 patients diagnosed with this devastating disease each year in the United States. This proposal specifically addresses the strategic elements 2 (screening) and 3 (early detection and diagnosis) outlined in the VHA's National Cancer Strategy (VHA Directive 2003-034).